One Pot Synthesis of 2-Oxazolidinone Derivatives

ABSTRACT

The present invention provides an improved process for preparing (S)-4{[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone which comprises: a) forming a carbamate of formula (III), from methyl 4-nitro-(L)-phenylalaninate hydrochloride; b) reducing the compound of formula (III) to give the compound of formula (IV); c) reducing the methyl ester grouping in the compound of formula (IV) to give the compound of formula (V); d) ring closure of the compound of formula (V) to give the compound of formula (VI); e) diazonium salt formation from the compound of formula (VI) followed by reduction to give the compound of formula (VII); f) Fischer reaction of the compound of formula (VII) to give (S)-4{[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}2-oxazolidino

The present invention relates to an improved process for preparingsubstituted indole derivatives which are useful for the treatment andprophylaxis of migraine. More particularly, the present inventionprovides an improved process for the preparation of the 5HT₁-likereceptor agonist(S)4-{[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone,which is known to be effective for the treatment of migraine.

Selective 5-HT₁-like receptor agonists are known to be usefultherapeutic agents. The 5-HT₁-like receptor mediates vasoconstrictionand thus modifies blood flow in the carotid vascular bed. Europeanpatent specification 0313397 describes a class of specific 5-HT₁-likereceptor agonists which are beneficial in the treatment or prophylaxisof conditions wherein vasoconstriction in the carotid vascular bed isindicated, for example, migraine, a condition associated with excessivedilation of the carotid vasculature.

International patent specification WO91/18897 describes a further classof compounds having exceptional “5-HT₁-like” receptor agonism andexcellent absorption following oral dosing. These properties render thecompounds disclosed in WO91/18897 particularly useful for certainmedical applications, notably the prophylaxis and treatment of migraine,cluster headache and headache associated with vascular disorders,hereinafter referred to collectively as “migraine”. One particularlypreferred compound described in WO91/18897 is(S)-N,N-dimethyl-2-[5-(2-oxo-1,3-oxazolidin-4-yl-methyl)-1H-indol-3-yl]ethylaminewhich is also known as(S)4-{[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinoneand can be represented by formula (I):

The compound of formula (I) can exist as its (S) or (R) enantiomer andis specifically exemplified in WO91/18897. A number of possible routesfor preparing the compound of formula (I) are suggested in WO91/18897.

A new process for preparing the compound of formula (I) has now beendiscovered. This process is advantageous over the processes disclosed inWO91/18897 in that it allows the final product to be made at a highyield on a large scale and in pure form by using a one pot procedure,thus avoiding the need for time-consuming and costly isolation ofintermediates. The new process also avoids the need for dangerousreagents such as phosgene or environmentally hazardous reagents such astin chloride.

According to the first aspect of the present invention, therefore, thereis provided a process for the preparation of a(S)-4-{[3-[2(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinonewhich process comprises the steps of

a) forming a carbamate from methyl 4-nitro-(L)-phenylalaninatehydrochloride, represented by formula (II)

by adding sodium carbonate or sodium hydrogen carbonate and n-butylchloroformate and reacting to givemethyl(S)—N-butoxycarbonyl-4-nitrophenylalaninate, represented byformula (III)

b) reducing the compound of formula (III) to give methyl(S)—N-butoxycarbonyl-4-amino phenylalaninate, represented by formula(IV)

c) reducing the methyl ester grouping —CO₂CH₃ in the compound of formula(IV) to give (S)—N-butoxycarbonyl-4-aminophenylalaninol, represented byformula (V)

d) a ring closure of the compound of formula (V) to give(S)-4-(4-aminobenzyl)-2-oxazolidinone, represented by formula (VI)

e) preparation of the diazonium salt of the compound of formula (VI)followed by reduction to give the hydrazine(S)-4-(4-hydrazinobenzyl)-2-oxazolidinone hydrochloride, represented byformula (VII)

f) Fischer reaction of the compound of formula (VII) to give thecompound of formula (I)

Suitably, one or more of steps a) to f) are carried out using a one potprocedure. Preferably steps a) to d) are carried out by a one potprocedure followed by isolation of the compound of formula (VI) and thena second one pot procedure for steps e) and f).

Step a) is conveniently carried out in the presence of a solvent e.g.aqueous ethyl acetate or dioxane. Aqueous ethyl acetate is preferred.Sodium carbonate is used in preference to sodium hydrogen carbonate andis preferably added prior to the n-butyl chloroformate. The reaction isconveniently carried out at a non-extreme temperature, suitably in therange 5-60° C. Preferably the reaction is carried out at 15-35° C. In aparticularly preferred embodiment the addition of sodium carbonate takesplace at a temperature of approximately 20° C. and the addition ofN-butyl chloroformate takes place at a temperature of approximately 30°C.

The reduction step b) is conveniently carried out in the presence of anorganic solvent, e.g. ethyl acetate or ethanol. Preferably step b) iscarried out by a one pot procedure using the ethyl acetate solution ofthe compound of formula (III) which results from step

a). Suitably, step b) is carried out by hydrogenation, preferably in thepresence of a catalyst such as palladium charcoal. The reaction may becarried out under an atmosphere of nitrogen using hydrogen at normalatmospheric pressure at room temperature. Hydrogenation is preferablycarried out at approximately 20 psi of hydrogen at an elevatedtemperature e.g. 30° C. to 50° C. The resulting ethyl acetate solutionof the compound of formula (IV) is preferably converted into a butanolsolution which can be used directly, as part of a one pot procedure, instep c). This conversion can conveniently be carried out by partialdistillation of the ethyl acetate solution followed by addition ofbutanol and fractionation to remove the ethyl acetate.

The methyl ester reduction of step c) is conveniently carried out in thepresence of a solvent e.g. SVM or n-butanol. Preferably step c) iscarried out as part of a one pot procedure by preparing a n-butanolsolution from the ethyl-acetate solution of the compound of formula (IV)and then directly reducing the n-butanol solution. The reduction ispreferably effected using sodium borohydride and is conveniently carriedout at a non-extreme temperature suitably 20-40° C. Preferably, thereduction is carried out in two phases; the first phase being carriedout under nitrogen at a temperature of approximately 25° C.; and thesecond phase being carried out at approximately 30° C. The resultingn-butanol solution of the compound of formula (V) can then be driedusing hydrochloric acid and ammonia. The dry n-butanol solution can beused directly in step d) as part of a one pot procedure.

Step d) is preferably carried out on a dry solution, e.g. a dry butanolsolution, of the compound of formula (V). Such a dry butanol solution isadvantageously prepared by drying the n-butanol solution which isproduced by step c). The dry n-butanol solution is preferablydecolourised using charcoal before carrying out the ring closurereaction. The ring closure can be conveniently effected using sodiummethoxide, suitably in an alcoholic solvent e.g. methanol. Mostpreferably, the ring closure is carried out using a 30% solution ofsodium methoxide in methanol. The reaction is preferably carried out atan elevated temperature which is suitably in the range 50-120° C.Preferably the reaction is carried out at approximately 85° C. Theresulting compound of formula (VI) may then be isolated. This isolationcan be carried out by standard centrifugation, filtration and dryingmethods.

Step e) is preferably carried out on the isolated compound of formula(VI). Isolation can be achieved, for example, using well knowncentrifugation, filtration and drying techniques. Diazonium saltformation can be carried out using aqueous sodium nitrite solution,preferably in the presence of concentrated hydrochloric acid, at areduced temperature. Preferably the salt formation is carried out at areduced temperature, e.g. 0-5° C. Hydrazine formation is then carriedout on the diazonium salt solution by using sodium sulphite as areducing agent. The sodium sulphite is suitably in the form of anaqueous solution. The reduction is advantageously carried out in twophases: the first being addition of sodium sulphite; the second beingaddition of hydrochloric acid. Preferably the first phase is carried outat a temperature below 10° C. The second phase is preferably carried outat an elevated temperature e.g. 55-60° C.

The solution of the compound of formula (VII) which results from step e)is preferably used directly in step f) as a one pot procedure. Step f)is a Fischer reaction. It has been found to be advantageous to carry outthis reaction at a relatively high dilution in order to maximise thepurity of the final product. Accordingly the solution which results fromstep e) is preferably diluted with water. The Fischer reaction is thencarried out by adding 4,4-diethoxy-N,N-dimethylbutylamine, suitablyunder a nitrogen atmosphere. Preferably, when the4,4-diethoxy-N,N-dimethylbutylamine is added, the diluted solution is atan elevated temperature. A suitable temperature is in the range 75-105°C., and is preferably approximately 90° C. The reaction preferablyproceeds under reflux.

When the reaction is complete, the compound of formula (I) can beextracted using standard techniques. Suitably the refluxed reactionproduct is cooled and adjusted to about pH7, e.g. using sodiumhydroxide. The pH adjusted product can then be extracted with ethylacetate and the aqueous layer adjusted to about pH 10 with sodiumhydroxide. The product can then be extracted at approximately 50° C.,followed by standard decolourising, filtration, distillation,centrifugation and drying techniques.

A particularly preferred reaction scheme for the preparation of thecompound of formula (I) is

According to the second aspect of the present invention, there isprovided a process for the purification of(S)4-{[3-(dimethylamino)ethyl]-1H-indol-5-yl]-methyl}-2-oxazolidinonewhich process comprises the steps of

a) dissolving crude(S)-4-{[3-(dimethylamino)ethyl]-1H-indol-5-yl]-methyl)-2-oxazolidinonein a refluxing mixture of ethanol in ethyl acetate and filtering the hotsolution;

b) slowly cooling the filtered solution to a temperature about 5° C.

c) centrifuging the product from step b), washing with ethyl acetatethen drying; and

d) treating with acetone to remove solvated ethyl acetate.

Preferably the refluxing mixture is 10% ethanol in ethyl acetate. Thehot solution is suitably decolourised using decolourising charcoal priorto filtration using filter aid.

The cooled filtered solution of step b) is suitably stirred over aprolonged period, which is preferably approximately 18 hours, prior tocentrifugation.

The drying stage of step c) is preferably carried out under vacuum.Suitably the product is dried at an elevated non-extreme temperature,for example 40-60° C., which is preferably approximately 50° C.

The dried solid product of step c) is conveniently treated with amixture of 20% acetone in water, at a non-extreme temperature,preferably 15-30° C., for example at room temperature. The resultingsuspension is then cooled to a non-extreme reduced temperature,preferably about 5° C., and stirred. The product is then centrifuged,washed with ethyl acetate and dried, preferably under vacuum at atemperature of approximately 45° C.

The resulting product is a non-solvated solid of high purity.

In a third aspect, the present invention provides non-solvated, pure(S)-4-{[3-(dimethylamino ethyl)-1H-indol-5-yl]-methyl}-2-oxazolidinone.

In further aspects, the invention provides compounds of formulae (III),(IV), (V) and (VI) as defined hereinbefore.

In still further aspects, the invention provides processes for preparingcompounds of formulae (III), (IV), (V) and (VI) as follows:

Compound (III): process step a) of the first aspect of the invention andpreferably as described on page 4;

Compound (IV): process step b) of the first aspect of the invention andpreferably as described in the paragraph bridging pages 4 and 5;

Compound (V): process step c) of the first aspect of the invention andpreferably as described on page 5; and

Compound (VI): process step d) of the first aspect of the invention andpreferably as described on page 5.

The invention will now be further described by the following examples.

EXAMPLE 1

A process for preparing(S)-4-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone inbulk. STAGE 1: The preparation of methyl 4-nitro-(L)- phenylaninatehydrochloride REACTION

MATERIALS QUANTITY MOLES 4-Nitro-(L)-phenylanine 100.0 kg 475.8 Methanol599.0 litres Hydrogen chloride 45.3 kg 1241.6 Methanol (wash 66.8 litresProcedure

Prepare a methanolic solution of hydrogen chloride by passing hydrogenchloride gas into a reactor containing methanol, maintaining temperaturebelow 25° C. Charge to the reactor the 4-nitro-(L)-phenylanine andreflux for about 1 hour. Cool to about 0° C. and centrifuge the product(methyl 4-nitro-(L)-phenylalaninate hydrochloride). Wash the productwith methanol and dry in vacuo at 50° C. STAGE 2: The preparation ofmethyl (S)-N-butoxycarbonyl- 4-nitrophenylalaninate REACTION

MATERIALS QUANTITY MOLES Methyl 4-nitro-(L)-phenylalaninatehydrochloride 45.0 kg 172.7 Sodium carbonate 20.1 kg 189.6 n-Butylchloroformate 24.0 kg 175.8 Ethyl acetate 248.0 kg Water (demineralised)100.0 kg Water (wash) 50.0 kgProcedure

Charge to the reactor demineralised water, methyl4-nitro-(L)-phenylalaninate hydrochloride, sodium carbonate and ethylacetate and cool the contents to about 20° C. with stirring. Add then-butyl chloroformate to the reaction mixture whilst maintaining thetemperature at about 30° C. and stir for about 30 minutes. Separate theaqueous layer and wash the ethyl acetate solution with water. The ethylacetate solution of methyl (S)—N-butoxycarbonyl-4-nitrophenylalaninateis used directly at the next stage. STAGE 3: The preparation of methyl(S)-N-butoxycarbonyl- 4-aminophenylaninate REACTION

MATERIALS QUANTITY MOLES Methyl (S)-N-butoxycarbonyl-4-  56.0 kg 172.7nitrophenylalaninate Ethyl acetate 252.0 kg 5% Palladium charcoal (55%water wet)  5.0 kg Ethyl acetate (filter wash)  18.0 kg Sodium carbonate 12.5 kg Water (demineralised) 100.0 kg Filter aid  3.5 kg Hydrogen asrequired Butanol 247.1 kgProcedure

Charge to the reactor the 5% palladium charcoal catalyst, the ethylacetate solution of methyl (S)—N-butoxycarbonyl-4-nitrophenylalaninateand hydrogenate at about 20 psi of hydrogen, maintaining a temperaturebetween 30° C. and 50° C. On completion, filter off the catalyst throughfilter aid and wash with ethyl acetate. Wash the ethyl acetate solutionwith aqueous sodium carbonate solution. The ethyl acetate solution ofmethyl (S)—N-butoxycarbonyl-4-aminophenylalaninate is partiallydistilled, butanol added and the mixture fractionated to remove theethyl acetate. The butanol solution is used directly at the next stage.STAGE 4: The preparation of (S)-N-butoxycarbonyl- 4-aminophenylalaninol.REACTION

MATERIALS QUANTITY MOLES Methyl (S)-N-butoxycarbonyl-4- 50.8 kg 172.8aminophenylaminate n-Butanol 305 litres Sodium borohydride (total) 6.5kg 172.8 conc. Hydrochloric acid 20.2 litres 300 Water (demineralised -for dilution of acid) 20.2 kg Water (demineralised) 150.0 kg conc.Ammonia solution (d = 0.88) 14.6 litresProcedure

Charge to the reactor the butanol solution of methyl(S)—N-butoxycarbonyl-4-aminophenylalaninate from Stage 3, and dilutewith n-butanol to the required volume. Cool the reactor contents toabout 25° C. Under a nitrogen atmosphere add half the amount of sodiumborohydride whilst maintaining a reaction temperature of about 25° C.Stir for 3 hours and then add the second half of sodium borohydride.Further stir the mixture for 5 hours and warm to 35° C. After this timestir the reaction mixture for about 12 hours and then slowly add aqueoushydrochloric acid, maintaining temperature at about 30° C., to decomposeany excess sodium borohydride. Add water, warm to about 35° C. and addammonia solution to adjust to approximately pH10. Separate the aqueouslayer and whilst maintaining a temperature of about 35° C., wash theorganic layer with water. Distil some of the butanol, whilstsimultaneously azeotroping dry the solution. The dry butanol solution isused directly at the next stage. STAGE 5: The preparation of(S)-4-(4-aminobenzyl)-2-oxazolidinone. REACTION

MATERIALS QUANTITY MOLES (S)-N-Butoxycarbonyl-4-aminophenylalaninol 91.9kg 345.0 n-Butanol 260.0 litres Sodium methoxide (30% weight in methanol7.5 kg 4.7 solution) Charcoal 2.0 kg n-Butanol (filter wash) 20.0 kgn-Butanol (product wash) 30.0 kg Filter aid 2.0 kgProcedure

Charge to the reactor the dry solution of(S)—N-butoxycarbonyl-4-aminophenylalaninol in n-butanol from Stage 4 andadd decolourising charcoal. Treat the dry solution at about 85° C. withthe slow addition of sodium methoxide in methanol. Heat the reactionmixture at 85° C. with the slow addition of sodium methoxide inmethanol. Heat the reaction mixture at 85° C. for a further 30 minutesand then filter hot through filter aid. After cooling the solution at5-10° C. for at least 8 hours, centrifuge the mixture, wash the filteredproduct with n-butanol and dry at about 50° C. in vacuo. STAGE 6A: Thepreparation of (S)-4-{3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone. REACTION

MATERIALS QUANTITY MOLES (S)-4-(4-Aminobenzyl)-2-oxazolidinone 19.2 kg100.0 Sodium nitrite 6.9 kg 100.0 Sodium sulphite 37.8 kg 300.0 conc.Hydrochloric acid 66.6 kg 4,4-Diethoxy-N,N-dimethylbutylamine 19.0 kg100.0 32% w/w Sodium hydroxide solution 60.0 kg Ethyl acetate (totalextracts) 303.0 litres Charcoal 2.9 kg Water (demineralised) 412.8 kgEthyl acetate (wash) 10.0 litres Filter aid (total used) 2.0 kgProcedure

Charge to the reactor conc. hydrochloric acid, demineralised water and(S)-4-(4-aminobenzyl)-2-oxazolidinone. Cool the reactor contents tobetween 0-5° C. and add aqueous sodium nitrite solution, maintaining thetemperature below 5° C. After stirring for about 30 minutes add thediazonium salt solution to a chilled aqueous solution of sodiumsulphite, maintaining the temperature below 10° C. After stirring for 15minutes slowly heat the resulting mixture to about 55-60° C., and thenslowly add hydrochloric acid. The solution is maintained at about 60° C.for about 18 hours.

Dilute the reaction mixture with water and heat to about 90° C. Under anitrogen atmosphere slowly add 4,4-diethoxy-N,N-dimethylbutylamine andheat at reflux for about 3 hours. Cool, and adjust the mixture to aboutpH7 using sodium hydroxide solution. Extract with ethyl acetate and thenadjust the aqueous layer to about pH10, again using sodium hydroxidesolution. Extract the product at about 50° C. using ethyl acetate. Treatthe combined ethyl acetate extracts (containing the product) withdecolourising charcoal, and filter through filter aid. Distil off mostof the solvent and chill the suspension to about 5° C. Centrifuge thecrude product, wash with ethyl acetate and vacuum dry at 50° C. STAGE6B: Purification of (S)-4-{3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone MATERIALS QUANTITY Ethyl acetate109.4 litres Ethanol 12.3 litres Charcoal 2.4 kg Ethyl acetate (productwash) 5.0 litres Acetone 11.8 litres Water (demineralised) 47.3 kg Water(demineralised) (product wash) 10.0 kg Filter acid 2.0 kg

The crude product of step 6A is dissolved in a refluxing mixture of 10%ethanol in ethyl acetate, treated with decolourising charcoal andfiltered hot through filter aid. The solution is slowly cooled to above5° C. and stirred for 18 hours. The purified product is thencentrifuged, washed with ethyl acetate and vacuum dried at 50° C. Inorder to remove solvated ethyl acetate, the dry solid is added to amixture of 20% acetone in water at ambient temperature and stirred for 1hour. The suspension is cooled to about 5° C. for about 1 hour beforecentrifuging the product, washing with ethyl acetate and drying in vacuoat about 45° C.

EXAMPLE 2 Alternative Preparation of Methyl(S)—N-butoxycarbonyl-4-nitrophenylalaninate (Compound of formula (III))

A mixture of methyl-4-nitro-(L)-phenylalaninate hydrochloride (40.00g,0.153 mole) and sodium hydrogen carbonate (73g, 0.870 mole) in1,4-dioxane (1000 ml) was stirred at approximately 10° C. underanhydrous conditions. A solution of butyl chloroformate (23.12 g, 21.52ml, 0.169 mole) in 1,4-dioxane (200 ml) was added over a period of tenminutes (reaction temperature approximately 13° C.). The resultingsuspension was allowed to warm to room temperature and stirred for threehours. The reaction was quenched slowly into water (1600 ml) and thenextracted with ethyl acetate (3×650 ml). The combined ethyl acetateextracts were washed with brine (1000 ml), dried over anhydrousmagnesium sulphate, filtered and evaporated to an oil. Residual solventwas removed using an oil pump at 50° C. to afford a syrup (51.34 g, 103%yield) which gradually solidified on standing.

TLC[SiO₂, EtOAc] was homogeneous (R_(f)=0.59).

¹H NMR (60 MHz CDCl₃) was consistent with structure of carbamate.

EXAMPLE 3 Alternative Preparation of Methyl(S)—N-butoxycarbonyl-4-aminophenylalaninate (Compound of formula (IV))

A solution of the compound prepared by Example 2 [45.00 g, 0.139 mole]in ethanol (845 ml) was added to moist 10% palladium on carbon (Type87L, 61.1% H₂O) [˜4.5 g] under an atmosphere of nitrogen. The reactionwas set up for hydrogenation at room temperature under normalatmospheric pressure. There was a steady uptake of hydrogen (˜9700 ml)over nine hours. The catalyst was filtered off on hyflo and washed withethanol (100 ml). The filtrate was concentrated in vacuo (water bathtemp. <40° C.) and the last traces of solvent removed using an oil pumpto afford a brown gum (41.70 g, 101%).

TLC [SiO₂, EtOAc] showed the required product (R_(f)=0.49) with tracesof a faster running impurity.

¹H NMR (300 MHz, CDCl₃) was consistent with structure of product andresidual ethanol.

EXAMPLE 4 Alternative Preparation of(S)—N-Butoxycarbonyl-4-aminophenylalaninol (Compound of formula (V))

To a stirred suspension of sodium borohydride (14.80 g, 0.390 mole) inSVM (150 ml), was added dropwise a solution of the compound prepared byExample 3 [76.40 g, 0.260 mole) in SVM (460 ml) at room temperature. Thereaction was left stirring overnight (˜18 hours) after which TLC (SiO₂,EtOAc) indicated complete consumption of starting material. The reactionmixture was acidified to ˜pH4 with 2M aqueous hydrochloric acid withice-cooling to a temperature of approximately 10° C. The resultingmixture was concentrated to a solid residue and saturated aqueous sodiumhydrogen carbonate (2000 ml) was added slowly. The aqueous mixture(pH˜8) was extracted with ethyl acetate (2×750 ml) and the combinedorganic extracts dried (magnesium sulphate), filtered and concentratedto a pale pink waxy sold (64.56 g, 93% yield).

TLC [SiO₂, EtOAc] indicated the required product (R_(f)=0.33) withtraces of impurities.

¹H NMR (60 MHz, CDCl₃) was consistent with structure of alaninol.

1-12. (canceled)
 13. Non-solvated, pure (S)-4-{[3-(dimethylaminoethyl)-1H-indol-5-yl]-methyl}-2-oxazolidinone. 14-26. (canceled)